Vidal, Adriana C.

Background: Tobacco smoking during pregnancy is associated with metabolic dysfunction in children, but mechanistic insights remain limited. Hypomethylation of cg05575921 in the aryl hydrocarbon receptor repressor (AHRR) gene is associated with in utero tobacco smoke exposure. In this study, we evaluated whether AHRR hypomethylation mediates the association between maternal smoking and metabolic dysfunction in children. Methods: We assessed metabolic dysfunction using liver fat content (LFC), serum, and clinical data in children aged 7–12 years (n=78) followed since birth. Maternal smoking was self-reported at 12 weeks gestation. Methylation was measured by means of pyrosequencing at 3 sequential CpG sites, including cg05575921, at birth and at ages 7–12. Regression models were used to evaluate whether AHRR methylation mediated the association between maternal smoking and child metabolic dysfunction. Results: Average AHRR methylation at birth was significantly higher among children of nonsmoking mothers compared with children of mothers who smoked (69.8% ± 4.4% vs. 63.5% ± 5.5, p=0.0006). AHRR hypomethylation at birth was associated with higher liver fat content (p=0.01), triglycerides (p=0.01), and alanine aminotransferase levels (p=0.03), and lower HDL cholesterol (p=0.01) in childhood. AHRR hypomethylation significantly mediated associations between maternal smoking and liver fat content (indirect effect=0.213, p=0.018), triglycerides (indirect effect=0.297, p=0.044), and HDL cholesterol (indirect effect = -0.413, p=0.007). AHRR methylation in childhood (n=78) was no longer significantly associated with prenatal smoke exposure or child metabolic parameters (p>0.05). Conclusions: AHRR hypomethylation significantly mediates the association between prenatal tobacco smoke exposure and features of childhood metabolic dysfunction, despite the lack of persistent hypomethylation of AHRR into childhood. Further studies are needed to replicate these findings and to explore their causal and long-term significance.

Abstract Purpose: The role of immune-oncologic mechanisms of racial disparities in prostate cancer remains understudied. Limited research exists to evaluate the molecular underpinnings of immune differences in African American men (AAM) and European American men (EAM) prostate tumor microenvironment (TME). Experimental Design: A total of 1,173 radiation-naïve radical prostatectomy samples with whole transcriptome data from the Decipher GRID registry were used. Transcriptomic expressions of 1,260 immune-specific genes were selected to assess immune-oncologic differences between AAM and EAM prostate tumors. Race-specific differential expression of genes was assessed using a rank test, and intergene correlational matrix and gene set enrichment was used for pathway analysis. Results: AAM prostate tumors have significant enrichment of major immune-oncologic pathways, including proinflammatory cytokines, IFNα, IFNγ, TNFα signaling, ILs, and epithelial–mesenchymal transition. AAM TME has higher total immune content score (ICSHIGH) compared with 0 (37.8% vs. 21.9%, P = 0.003). AAM tumors also have lower DNA damage repair and are genomically radiosensitive as compared with EAM. IFITM3 (IFN-inducible transmembrane protein 3) was one of the major proinflammatory genes overexpressed in AAM that predicted increased risk of biochemical recurrence selectively for AAM in both discovery [HRAAM = 2.30; 95% confidence interval (CI), 1.21–4.34; P = 0.01] and validation (HRAAM = 2.42; 95% CI, 1.52–3.86; P = 0.0001) but not in EAM. Conclusions: Prostate tumors of AAM manifest a unique immune repertoire and have significant enrichment of proinflammatory immune pathways that are associated with poorer outcomes. Observed immune-oncologic differences can aid in a genomically adaptive approach to treating prostate cancer in AAM.

116 Background: Prostateinflammation is linked with prostate cancer. However, whether prostate inflammation varies by race is unclear. Methods: We analyzed baseline acute and chronic prostate inflammation by race in REDUCE. REDUCE was a 4-year, multicenter, placebo-controlled study where all men received a single, negative prostate biopsy within 6 months prior to enrollment. Among 8,046 men who met the inclusion criteria, we included those with data on baseline biopsy prostate inflammation, acute/chronic or none, determined by central pathology. Logistic regression was used to compare prostate inflammation by race, and models were adjusted for demographic and clinical features. Results: Of the 8,046 men, 7,326 were white (91.1%), 184 (2.3%) black, 132 (1.6%) Asian, 323 (4.0%) Hispanic, and 81(1%) unknown. Seventy eight percent of men had chronic and 15% had acute prostate inflammation. Men with chronic inflammation were older (p<0.001), while men with acute inflammation were younger (p<0.001) compared to men with none prostate inflammation. Both acute and chronic inflammation was associated with lower PSA (all p≤0.0001), smaller prostate volume (all p≤0.0001) and geographic region (all p≤0.006). On crude analysis, compared to whites, Asian men were two times more likely to have acute prostate inflammation (OR=1.92, 95%CI: 1.29-2.85, p=0.001), whereas the associations with Hispanic and black race were not significant (all p≥0.39). However, on multivariable analysis, black men were 36% less likely to have acute prostate inflammation (OR=0.64, 95%CI: 0.41-0.99, p=0.04), whereas the likelihood of having acute prostate inflammation remained high in Asians (OR=1.85, 95%CI: 1.25-2.85, p=0.004). No associations by race were found with chronic prostate inflammation. Conclusions: Given that at the population level, black race is a high risk factor for PC and Asian men have lower risk of PC, these data indicate that the presence of acute inflammation in a negative prostate biopsy could be an indication of future PC risk. Further studies to confirm these findings are needed. Clinical trial information: NCT00056407.

Abstract The role of metformin in prostate cancer chemoprevention remains unclear. REDUCE, which followed biopsy-negative men with protocol-dictated PSA-independent biopsies at 2- and 4-years, provides an opportunity to evaluate the link between metformin use and prostate cancer diagnosis with minimal confounding from screening biases. In diabetic men from REDUCE, we tested the association between metformin use, use of other antidiabetic medications, versus no antidiabetic medication use, and prostate cancer diagnosis as well as prostate cancer grade (low-grade Gleason 4–6 and high-grade Gleason 7–10) using logistic regression. Of the 540 diabetic men with complete data, 205 (38%) did not report use of any antidiabetic medications, 141 (26%) reported use of at least one antidiabetic medication other than metformin, and 194 (36%) reported use of metformin. During the 4-year study, 122 men (23%) were diagnosed with prostate cancer. After adjusting for various clinical and demographic characteristics, we found that metformin use was not significantly associated with total (OR, 1.19; P = 0.50), low- (OR, 1.01; P = 0.96), or high-grade (OR, 1.83; P = 0.19) prostate cancer diagnosis. Likewise, there was no significant association between the use of non-metformin antidiabetic medications and prostate cancer risk in both crude (OR, 1.02; P = 0.95) and multivariable analysis (OR, 0.85; P = 0.56). Furthermore, the interactions between antidiabetic medication use and BMI, geographic location, coronary artery disease, smoking, and treatment group were not significant (all P &gt; 0.05). Among diabetic men with a negative prestudy biopsy who all underwent biopsies largely independent of PSA, metformin use was not associated with reduced risk of prostate cancer diagnosis. Cancer Prev Res; 8(11); 1055–60. ©2015 AACR.

Abstract Purpose: A recent meta-analysis showed that aspirin was associated with reduced prostate cancer risk. As anti-inflammatory medications lower PSA levels, whether these findings reflect reduced prostate cancer detection or lower prostate cancer risk is unknown. We tested the association between aspirin and nonaspirin NSAID use on prostate cancer diagnosis in REDUCE, where all men received biopsies at 2 and 4 years largely independent of PSA. REDUCE tested dutasteride for prostate cancer risk reduction in men with a PSA of 2.5 to 10.0 ng/mL and a negative prestudy biopsy. Experimental Design: We examined the association between aspirin, NSAIDs, or both and total, low-grade (Gleason &lt; 7), or high-grade (Gleason ≥ 7) prostate cancer versus no prostate cancer using multinomial logistic regression among 6,390 men who underwent ≥1 on-study biopsy. Multivariable analyses were adjusted for age, race, geographic region, PSA, prostate volume, digital rectal examination, body mass index, treatment arm, smoking, alcohol, statins, hypertension, diabetes, and cardiovascular disease. Results: Overall, 3,169 men (50%) were nonusers, 1,368 (21%) used aspirin, 1,176 (18%) used NSAIDs, and 677 (11%) used both. In unadjusted models, aspirin was associated with reduced prostate cancer risk (OR = 0.85, P = 0.036). In multivariable analyses, aspirin was associated with reduced total prostate cancer risk (OR = 0.81, P = 0.015). Use of NSAIDs or NSAIDs and aspirin was not associated with total, low-grade, or high-grade prostate cancer, though all ORs were &lt;1 (all P ≥ 0.08). Therefore, we created a dichotomous variable of aspirin and/or NSAID users versus nonusers. On multivariable analysis, the use of aspirin and/or NSAIDs was significantly associated with decreased total (OR = 0.87, P = 0.030) and high-grade (OR = 0.80, P = 0.040), but not with low-grade, prostate cancer risk (OR = 0.90, P = 0.15). Results were similar in placebo and dutasteride arms. Conclusions: Among men with a negative biopsy, aspirin and/or NSAID use was associated with decreased prostate cancer risk. Additional studies are warranted. Clin Cancer Res; 21(4); 756–62. ©2014 AACR.

Abstract Background: Studies suggest that obesity is associated with lower risk of prostate cancer but more aggressive cancers. As obesity lowers PSA levels, these observations may be influenced by detection bias. We examined the association between obesity and risk of low- and high-grade prostate cancer in REDUCE, in which biopsies were largely independent of PSA. Methods: The REDUCE study tested dutasteride for prostate cancer risk reduction in men with a PSA of 2.5 to 10.0 ng/mL and a negative biopsy. Study participants included 6,729 men who underwent at least one on-study biopsy. The association between baseline body mass index (BMI &lt;25 kg/m2 normal weight; 25–29.9 kg/m2 overweight; and ≥30 kg/m2 obese) and risk of high-grade (Gleason ≥7) or low-grade prostate cancer (Gleason &lt;7) versus no prostate cancer was examined using multinomial logistic regression. Results: Overall, 1,739 men (27%) were normal weight, 3,384 (53%) overweight, and 1,304 (20%) were obese. Obesity was associated with lower risk of low-grade prostate cancer in both univariable (OR, 0.74; P = 0.001) and multivariable analyses (OR, 0.79; P = 0.01). In univariable analysis, obesity was not associated with high-grade prostate cancer (OR, 1.08; P = 0.50). However, in multivariable analysis, obesity was associated with increased risk of high-grade prostate cancer (OR, 1.28; P = 0.042). This analysis was not able to address how obesity may influence prostate cancer progression. Conclusions: Obesity is associated with decreased risk of low-grade and increased risk of high-grade prostate cancer. These data provide further support to the hypothesis that obesity is associated with aggressive prostate cancer. Impact: Obesity is linked with aggressive prostate cancer. Avoiding obesity may prevent the risk of developing high-grade prostate cancer. Cancer Epidemiol Biomarkers Prev; 23(12); 2936–42. ©2014 AACR.